BACKGROUND



The human body is primarily concerned with the stability of pH. The lungs are the organs responsible for maintaining an adequate PaCO2 for the level of CO2 production (VCO2) while avoiding critical decrements in PaO2. Most of the pulmonary function tests, however, explore potential abnormalities in a step that precedes alveolar gas exchange, i.e., ventilation (VE). Of note, arterial blood gases are influenced not only by the integrity of the alveolar-capillary membrane but also by hemodynamic factors (e.g., poor peripheral tissue perfusion leading to low mixed venous O2 pressure) and changes in ventilatory drive (e.g., hypoventilation leading to hypercapnia and hypoxemia) among others.(1) Due to the ominous systemic consequences of impaired pulmonary gas exchange, tests addressing its multifaceted features are germane to the practice of Pulmonology.



OVERVIEW



A 71-year-old current smoker woman was referred to the pulmonology clinic due to progressing exertional dyspnea (modified Medical Research Council score = 3/4) despite normal spirometry, lung volumes, and contrast-enhanced chest CT results. Her dyspnea has been ascribed to sedentary lifestyle and severe anemia in the context of multiple myeloma. A six-minute walk test confirmed poor exercise tolerance with high dyspnea burden and exertional hypoxemia. Tests assessing gas exchange showed: a) low hemoglobin-corrected DLCO and carbon monoxide transfer coefficient (KCO) with normal alveolar ventilation (VA) and VA/TLC ratio; b) mildly reduced PaO2 and eucapnia; and c) high alveolar-arterial gradient pressure of O2 [P(A-a)O2], shunt fraction (on 100% O2), physiological dead space, arterial to end-tidal carbon dioxide gradient [P(a-ET)CO2], and resting o VE/VCO2ratio. The pattern of impaired pulmonary gas exchange (Figure 1, in red), shunt and preserved VE distribution in the absence of emphysema or pulmonary arterial-venous fistulas raised concerns of poor pulmonary perfusion secondary to an extrapulmonary shunt. In fact, a transesophageal echocardiogram with microbubbles showed a small patent foramen ovale whose dimension markedly increased even with mild exertion. Absence of pulmonary hypertension at rest did not preclude right-to-left shunt (putative mechanisms in the study by Vitarelli).(2)

The rate of alveolar gas exchange can be substantially impaired despite preserved lung parenchyma. If hypoxemia cannot be explained by hypoventilation-high PaCO2 and alveolar partial pressure of CO2 (PACO2), leading to low alveolar partial pressure of O2 (PAO2)-or low inspired O2 pressure (e.g., high altitude), impaired pulmonary perfusion should be considered as the most likely explanation. In the present case, right-to-left shunt diminished pulmonary perfusion thereby decreasing the functional surface for alveolar-capillary gas transfer ( DLCO).(3) As VE was relatively well distributed (normal VA/TLC ratio),(4) KCO decreased. High VE/perfusion ratio increased PAO2-and P(A-a)O2 as PaO2 was low-and the fraction of tidal volume "wasted" in the dead space.(5) Thus, end-tidal CO2 tension (PETCO2) was substantially lower than PACO2 (estimated by PaCO2), because it was diluted by the PCO2 from alveoli which were not properly exposed to CO2-rich venous blood [P(a-ET)CO2].(6) Higher VE was then needed to keep alveolar ventilation (VE/VCO2 ratio; Figure 1, in blue).



CLINICAL MESSAGE



An integrated analysis of arterial blood gases (with indirect measurements of VE distribution and VE-perfusion matching) and lung transfer capacity-in the light of clinical data-is invariably useful to untangle the mechanisms and consequences of impaired pulmonary gas exchange.



REFERENCES



1. Neder J, Nery L. Clinical Exercise Physiology: Theory and Practice [in Portuguese]. São Paulo: Artes Médicas; 2002. 404 p.

2. Vitarelli A. Patent Foramen Ovale: Pivotal Role of Transesophageal Echocardiography in the Indications for Closure, Assessment of Varying Anatomies and Post-procedure Follow-up. Ultrasound Med Biol. 2019;45(8):1882-1895. https://doi.org/10.1016/j.ultrasmedbio.2019.04.015

3. Neder JA, Berton DC, Muller PT, O'Donnell DE. Incorporating Lung Diffusing Capacity for Carbon Monoxide in Clinical Decision Making in Chest Medicine. Clin Chest Med. 2019;40(2):285-305. https://doi.org/10.1016/j.ccm.2019.02.005

4. Neder JA, O'Donnell CD, Cory J, Langer D, Ciavaglia CE, Ling Y, et al. Ventilation Distribution Heterogeneity at Rest as a Marker of Exercise Impairment in Mild-to-Advanced COPD. COPD. 2015;12(3):249-256. https://doi.org/10.3109/15412555.2014.948997

5. Neder JA, Arbex FF, Alencar MC, O'Donnell CD, Cory J, Webb KA, et al. Exercise ventilatory inefficiency in mild to end-stage COPD. Eur Respir J. 2015;45(2):377-387. https://doi.org/10.1183/09031936.00135514

6. Neder JA, Ramos RP, Ota-Arakaki JS, Hirai DM, D'Arsigny CL, O'Donnell D. Exercise in-tolerance in pulmonary arterial hypertension. The role of cardiopulmonary exercise testing. Ann Am Thorac Soc. 2015;12(4):604-612. https://doi.org/10.1513/AnnalsATS.201412-558CC